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Molecular dynamics simulations on the inhibition of Cyclin-Dependent Kinases 2 and 5 in the presence of activators

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Abstract

Interests in CDK2 and CDK5 have stemmed mainly from their association with cancer and neuronal migration or differentiation related diseases and the need to design selective inhibitors for these kinases. Molecular dynamics (MD) simulations have not only become a viable approach to drug design because of advances in computer technology but are increasingly an integral part of drug discovery processes. It is common in MD simulations of inhibitor/CDK complexes to exclude the activator of the CDKs in the structural models to keep computational time tractable. In this paper, we present simulation results of CDK2 and CDK5 with roscovitine using models with and without their activators (cyclinA and p25). While p25 was found to induce slight changes in CDK5, the calculations support that cyclinA leads to significant conformational changes near the active site of CDK2. This suggests that detailed and structure-based inhibitor design targeted at these CDKs should employ activator-included models of the kinases. Comparisons between P/CDK2/cyclinA/roscovitine and CDK5/p25/roscovitine complexes reveal differences in the conformations of the glutamine around the active sites, which may be exploited to find highly selective inhibitors with respect to CDK2 and CDK5.

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Abbreviations

(CDK):

Cyclin-Dependent Kinase

P/CDK2/cyclinA/roscovitine:

Thr160−phosphated/CDK2/cyclinA/roscovitine

References

  1. Harper JW, Adams PD (2001) Chem Rev 101:2511

    Article  CAS  Google Scholar 

  2. Garrett MD, Fattaey A (1999) Curr Opin Genet Dev 9:104

    Article  CAS  Google Scholar 

  3. Webster KR (1998) Expert Opin Investig Drugs 7:865

    Article  CAS  Google Scholar 

  4. Nguyen MD, Julien JP (2003) Neurosignals 12:215

    Article  CAS  Google Scholar 

  5. Lau LF, Ahlijanian MK (2003) Neurosignals 12:209

    Article  CAS  Google Scholar 

  6. Smith PD, Crocker SJ, Jackson-Lewis V, Jordan-Sciutto KL, Hayley S (2003) Proc Natl Acad Sci USA 100:13650

    Article  CAS  Google Scholar 

  7. Bu B, Li J, Davies P, Vincent I (2002) J Neurosci 22:6515

    CAS  Google Scholar 

  8. Wang J, Liu S, Fu Y, Wang JH, Lu Y (2003) Nat Neurosci 6:1039

    Article  CAS  Google Scholar 

  9. Hunter T, Pines J (1994) Cell 79:573

    Article  CAS  Google Scholar 

  10. Sherr C (1996) Science 274:1672

    Article  CAS  Google Scholar 

  11. Norbury C, Nurse P (1992) Annu Rev Biochem 61:441

    Article  CAS  Google Scholar 

  12. De Azevedo WF Jr, Mueller-Dieckmann HJ, Schulze-Gahmen U, Worland PJ, Sausville E, Kim SH (1996) Proc Natl Acad Sci USA 93:2735

    Article  Google Scholar 

  13. De Azevedo WF Jr, Leclerc S, Meijer L, Havlicek L, Strnad M, Kim SH (1997) Eur J Biochem 243:518

    Article  Google Scholar 

  14. Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massague J, Pavletich NP (1995) Nature 376:313

    Article  CAS  Google Scholar 

  15. Patrick GN, Zhou P, Kwon YT, Howley PM, Tsai L-H (1998) J Biol Chem 273:24057

    Article  CAS  Google Scholar 

  16. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai L-H (1999) Nature 402:615

    Article  CAS  Google Scholar 

  17. Tarricone C, Dhavan R, Peng J, Areces LB, Tsai L-H, Musacchio A (2001) Mol Cell 8:657

    Article  CAS  Google Scholar 

  18. Russo A, Jeffrey PD, Pavletich NP (1996) Nat Struct Biol 3:696

    Article  CAS  Google Scholar 

  19. Morgan DO (1996) Curr Opin Cell Biol 8:767

    Article  CAS  Google Scholar 

  20. Cavalli A, Dezi C, Folkers G, Scapozza L, Recanatini M (2001) Proteins Struct Funct Genet 45:478

    Article  CAS  Google Scholar 

  21. Otyepka M, Kříž Z, Koča J (2002) J Biomol Struct Dyn 20:141

    CAS  Google Scholar 

  22. De Azevedo WF Jr, Gaspar RT, Canduri F, Camera JC Jr, Silveira NJF (2002) Biochem Biophys Res Commun 297:1154

    Article  Google Scholar 

  23. Cavalli A, Vivo MD, Recanatini M (2003) Chem Commum 1308

  24. Sims PA, Wong CF, McCammon JA (2003) J Med Chem 46:3314

    Article  CAS  Google Scholar 

  25. Park H, Yeom MS, Lee S (2004) ChemBioChem 5:1662

    Article  CAS  Google Scholar 

  26. Bártová I, Otyepka M, Kříž Z, Koča (2004) Protein Sci 13:1449

    Article  Google Scholar 

  27. Bártová I, Otyepka M, Kříž Z, Koča J (2005) Protein Sci 14:445

    Article  Google Scholar 

  28. Jiang Y-J, Zou J-W, Gui C-S (2005) J Mol Model 11:509

    Article  CAS  Google Scholar 

  29. García-Sosa AT, Mancera RL (2006) J Mol Model 12:422

    Article  Google Scholar 

  30. Davies TG, Tunnah P, Meijer L, Marko D, Eisenbrand G, Endicott JA, Noble MEM (2001) Structure 9:389

    Article  CAS  Google Scholar 

  31. Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernati J, Wui Y-Z, Mandelkowi E-M, Eisenbrand G, Meijer L (2001) J Biol Chem 276:251

    Article  CAS  Google Scholar 

  32. Sausville EA (2002) Trends Mol Med 8:S32

    Article  CAS  Google Scholar 

  33. Noble MEM, Endicott JA, Johnson LN (2004) Science 303:1800

    Article  CAS  Google Scholar 

  34. Noble M, Barrett P, Endicott J, Johnson L, McDonnell J, Robertson G, Zawaira A (2005) Biochimica et Biophysica Acta 1754:58

    CAS  Google Scholar 

  35. Huew A, Mazitschek R, Giannis A (2003) Angew Chem Int Ed 42:2122

    Article  Google Scholar 

  36. Sielecki M, Boylan JF, Benfield PA, Trainor GL (2000) J Med Chem 43:1

    Article  CAS  Google Scholar 

  37. Knockaert P, Greengard L, Meijer L (2002) Trends Pharmacol Sci 23:417

    Article  CAS  Google Scholar 

  38. Lau LF, Seymour PA, Sanner MA, Schachter JB (2002) J Mol Neurosci 19:267

    Article  CAS  Google Scholar 

  39. Crews CM, Mohan R (2000) Curr Opin Chem Biol 4:47

    Article  CAS  Google Scholar 

  40. Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N (1997) Eur J Biochem 243:527

    Article  CAS  Google Scholar 

  41. Ljungman M, Paulsen MT (2001) Mol Pharmacol 60:785

    CAS  Google Scholar 

  42. Bach S, Knockaert M, Reinhardt J, Lozach O, Schmitt S, Baratte B, Koken M, Coburn SP, Tang L, Jiang T, Liang DC, Galons H, Dierick JF, Pinna LA, Meggio F, Totzke F, Schachtele C, Lerman AS, Carnero A, Wan Y, Gray N, Meijer L (2005) J Biol Chem 280:31208

    Article  CAS  Google Scholar 

  43. Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KM, Ferguson DM Jr, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA (1995) J Am Chem Soc 117:5179

    Article  CAS  Google Scholar 

  44. Besler BH, Merz KM, Kollman PA (1990) J Comput Chem 11:431

    Article  CAS  Google Scholar 

  45. Fox T, Kollman PA (1998) J Phys Chem B 102:8070

    Article  CAS  Google Scholar 

  46. Case DA, Pearlman DA, Caldwell JW, Cheatham TE III, Wang J, Ross WS, Simmerling CL, Darden TA, Merz KM, Stanton RV, Cheng AL, Vincent JJ, rowley M, Tsui V, Gohlke H, Radme RJ, Duan Y, Pitera J, Massova I, Seibel GL, Singh UC, Weiner PK, Kollman PA (2002) AMBER 7. University of California, San Francisco

  47. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) J Chem Phys 79:926

    Article  CAS  Google Scholar 

  48. Darden T, York D, Pedersen L (1993) J Chem Phys 98:10089

    Article  CAS  Google Scholar 

  49. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) J Comput Phys 23:327

    Article  CAS  Google Scholar 

  50. Morris GM, Goodsell DS, Huey R, Hart WE, Halliday S, Belew R, Olson AJ (1999) Autodock Version 3.0.3. Molecular Graphics Laboratory, Department of Molecular Biology, The Scripps Research Institute

  51. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) J Comput Chem 19:1639

    Article  CAS  Google Scholar 

  52. Massova I, Kollman PA (2000) Perspect Drug Discov 18:113

    Article  CAS  Google Scholar 

  53. Connolly ML (1983) J Appl Cryst 16:548

    Article  CAS  Google Scholar 

  54. Sitkoff D, Sharp KA, Honig B (1994) J Phys Chem 98:1978

    Article  CAS  Google Scholar 

  55. Lemaitre V, Ali R, Kim C, Watts A, Fischer WB (2004) FEBS Lett 563:75

    Article  CAS  Google Scholar 

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Acknowledgement

Prof. Meijer Laurent in France and Dr. Sung-Hou KIM in University of Berkeley are gratefully acknowledged for generously offering the crystal structures of the CDK2/R-roscovitine complex.

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Authors and Affiliations

  1. Nanoscience and Nanotechnolgy Initiative, National University of Singapore, S117576, Singapore, Singapore

    Bing Zhang, Vincent B. C. Tan, Kian Meng Lim & Tong Earn Tay

  2. Department of Mechanical Engineering, National University of Singapore, S117576, Singapore, Singapore

    Vincent B. C. Tan, Kian Meng Lim & Tong Earn Tay

  3. Department of Chemistry, Zhejiang University, Hangzhou, 310027, P.R. China

    Bing Zhang

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  1. Bing Zhang
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  2. Vincent B. C. Tan
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  3. Kian Meng Lim
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Correspondence to Vincent B. C. Tan.

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Zhang, B., Tan, V.B.C., Lim, K.M. et al. Molecular dynamics simulations on the inhibition of Cyclin-Dependent Kinases 2 and 5 in the presence of activators. J Comput Aided Mol Des 20, 395–404 (2006). https://doi.org/10.1007/s10822-006-9081-z

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  • DOI: https://doi.org/10.1007/s10822-006-9081-z

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